Introduction
Advantages of various direct thrombin inhibitors, a modified dosing schedule for bivalrudin, and experience with monitoring parameters are described. These advantages may form the basis for consideration when alternative anticoagulation to heparin is desired during peripheral vascular procedures.

Case ReportAn 82-year-old, 65 kg, white male underwent evaluation for progressive fatigue and shortness of breath. He had undergone a Hancock porcine mitral valve replacement in conjunction with a one-vessel coronary artery bypass 12 years previously. He also had a history of chronic atrial fibrillation, requiring warfarin therapy. After evaluation confirmed significant mitral regurgitation, he was admitted for heparinization and cessation of warfarin therapy prior to “re-do” valve replacement. His preoperative platelet count was 162K/cu mm. He underwent an uncomplicated procedure using a #27 Carpentier-Edwards mitral valve with a concomitant carotid endarterectomy and Dacron patch angioplasty for asymptomatic critical left internal carotid stenosis. Aspirin was begun soon postoperatively. His immediate postoperative platelet count was 80K/cu mm and continued to remain low through the second postoperative day (POD) at 64K/cu mm. Subcutaneous heparin was restarted at 5000 units every eight hours in the evening of POD 2. The platelet count remained low at 68 K/cu mm on POD 3, but his platelet factor 4 (PF4) assay was negative. Coumadin was begun on POD 5, the heparin was discontinued, and a repeat PF4 assay was again negative. By POD 6, the platelet count had increased to 148K/cu mm, and his prothrombin time was 15.5 sec (nl 12.6–15.2); international normalized ratio (INR) was 1.19.

On the seventh POD with an INR of 1.21, he developed sudden onset of the left foot, numbness and calf pain during physical therapy. Initial evaluation suggested a viable functioning limb with no change in pulse status and an audible Doppler signal. However, by the following morning (on POD 8), symptoms had not only progressed but, only a femoral pulse was palpable in the symptomatic limb, which remained cold but appeared viable. Femoral and pedal pulses were palpable in the asymptomatic limb. There was no evidence of aortic or peripheral aneurysms, and the ankle brachial index was reduced to 0.71, but no toe pressure was discernable on the symptomatic extremity.

Though an echocardiogram showed the mitral valve to be well seated without thrombus, a thromboembolic event was suspected, and he was taken directly to the operating room for exploration and angiography without reversal of anticoagulation. Despite previous negative PF4 assays and no serologic evidence of heparin-induced thrombocytopenia (HIT), previous diminished platelet counts and the sudden onset of acute leg ischemia heightened clinical concern about the possibility of serologically negative HIT, as well as concern about using heparin during any attempt at lower extremity revascularization.

Because of these concerns, bivalirudin was used for intraoperative anticoagulation. Evaluation of the patients’ underlying renal function was calculated using the Cockcroft-Gault equation (serum creatinine: 1.1 mg/dl), and was estimated to be approximately 48 ml/min at the time of operation. Since experience using bivalirudin for anticoagulation in patients undergoing off-pump coronary artery bypass operations, percutaneous coronary, and peripheral interventions has been described,1–3 we chose to use a modified version of these dosing strategies to target a lower level of anticoagulation for this open surgical procedure. A bolus dose of bivalirudin 0.5 mg /kg was given intravenously over 10–20 seconds, followed by a continuous infusion of 1.0 mg/kg/hr to achieve and maintain an activated clotting time (ACT), approximately twice baseline (range: 225–250 seconds). Activated clotting times were measured intraoperatively at baseline, 5 minutes after the loading dose given, and then approximately every 15 minutes throughout the procedure. Activated partial thromboplastin time, PT, INR and platelet count were also monitored periodically during the procedure (Table 1). Documentation of an ACT in the predetermined range was confirmed prior to the placement of arterial clamps and the interruption of flow at the femoral level.

The common femoral pulse was excellent, but significant plaque at the common femoral bifurcation necessitated a longitudinal arteriotomy over the bifurcation onto the superficial femoral artery, and an intraoperative arteriogram was performed. Though moderate diffuse atherosclerosis was present in the superficial femoral artery, no flow-limiting plaque was noted at either the arteriotomy or to the level of the popliteal. Filling defects consistent with discontinuous thrombo-emboli were present in the proximal popliteal and posterior tibial vessels. Of note, immediately after the arteriotomy, an alert team member recognized that the standard heparinized saline-irrigating solution already prepared on the field would not be prudent in this setting of possible HIT, and despite the patient’s negative antibody screen, the solution was discarded.
Successful thromboembolectomy was accomplished with retrieval of organized thrombus from both the popliteal and tibial levels, but no “white clot” suggestive of platelet aggregate, suggesting an embolic — rather than thrombotic — event. Repeat angiography revealed moderately diseased, irregular but patent, superficial femoral, popliteal, and peroneal, and posterior tibial vessels without significant distal stenosis or residual thrombus, though the anterior tibial appeared occluded. Thus, the need for direct popliteal exploration or bypass was avoided. The bivalirudin infusion was reduced to 0.1 mg/kg/hr after Dacron patch closure of the arteriotomy was completed with a running suture. Following removal of the arterial clamp and restoration of flow, hemostasis was clinically satisfactory within 30 minutes of reducing the bivalirudin infusion and completion of the arterial closure, with continued correction in coagulation parameters.

Postoperatively the patient had full return of palpable pedal pulses. He was maintained on a continuous bivalirudin infusion at 0.1 mg/kg/hr with titration to maintain a PTT of approximately 2–2.5 times his baseline value (goal: 60–80 seconds) to allow for transition to warfarin for long-term anticoagulation (Table 2). Warfarin was re-initiated the night of surgery without a loading dose, and a daily dose of 5 mg was given until the INR was greater than 2.0. No wound hematoma was evident and perfusion was maintained. His level of anticoagulation on bivalirudin was remarkably stable, requiring only one dosage adjustment to 0.12 mg/kg/hr over the course of therapy. Cessation of the bivalirudin on POD 3 following leg revascularization transiently decreased the INR to 1.63, requiring brief re-initiation of bivalirudin for several hours. A repeat INR on POD 4 following leg revascularization was 2.09. Bivalirudin was discontinued at this time, and the patient was discharged on warfarin 5 mg, alternating with 7.5 mg daily. The final pathology report was consistent with only organized thrombus. He remained asymptomatic with palpable pedal pulses three months post discharge.

Discussion
Direct thrombin inhibitors are assuming an increasing role in the management of suspected HIT to reduce thrombo-embolic complications.4,5 Although anticoagulation with heparin is the generally accepted method of preventing thrombus formation during the performance of cardiac and peripheral vascular procedures, in the setting of suspected HIT — with or without heparin-PF4 antibodies — standard heparinization is not a safe option. Alternatives are limited, and in such settings, the use of the recombinant direct thrombin inhibitors, lepirudin, bivalirudin and argatroban during cardiopulmonary bypass has been described.6–9 However, these intense dosages needed for cardiopulmonary bypass do not translate directly to a relatively lower intensity of anticoagulation required for peripheral vascular surgery. To date, the experience with direct thrombin inhibition for anticoagulation among patients requiring vascular procedures has been even more recent and limited.10,11 While a more aggressive anticoagulation regimen with either re-initiation of heparin or direct thrombin inhibitors following mitral valve replacement in the setting of atrial fibrillation may have obviated this post-operative thromboembolic event, this controversy remains beyond the impetus of this discussion. Rather, our case focuses on delineating not only a safe and effective method of anticoagulation using bivalirudin in a patient with possible HIT requiring lower extremity revascularization, but also maintenance of postoperative anticoagulation for several days, with successful transition to anticoagulation with warfarin.

Although there was no serologic evidence of heparin-induced thrombocytopenia in this case, we were faced with the knowledge that PF4 may not be positive in all cases of HIT. There was a compelling need for systemic anticoagulation in a setting where diminished platelet counts were encountered following and during heparin therapy and a clinical suspicion for HIT remained. We felt that the administration of bivalirudin was a more appropriate choice for use in peripheral vascular procedures in this setting. It is a direct thrombin inhibitor and does not appear to precipitate HIT by cross-reacting with associated heparin-PF4 antibodies. In addition, its pharmacokinetic profile, quick onset, and short half-life make it ideal for use in peripheral vascular procedures as an alternative to heparin or the other thrombin inhibitors.

Unlike heparin, bivalirudin is a direct thrombin inhibitor which reversibly binds to the thrombin active site, bypassing interaction with antithrombin III.12 There are two other direct thrombin inhibitors currently available in the United States, lepirudin and argatroban. All are administered intravenously, and none of the three cross react with the heparin-induced antibody.5 Lepirudin is primarily eliminated by renal excretion with a terminal half life of approximately 1.3 hours.5,12 Argatroban is hepatically cleared with a terminal half life of approximately 39–51 minutes.5 Bivalirudin is cleared both by intravascular proteolysis and renal mechanisms and possesses the shortest elimination half life of approximately 25 minutes.13 There is no reversal for this group of drugs, and their use must be judicious to prevent coagulopathy and bleeding, especially during cardiac and peripheral vascular procedures.5 Thus, bivalirudin appears to offer advantages over lepirudin and argatroban during surgery in patients with adequate renal function. In patients with renal insufficiency, the elimination half life of lepirudin is prolonged (up to 50 hours in renal failure).14 The elimination half life for bivalirudin in patients with moderate renal impairment (creatinine clearance: 10–29 ml/minute) is approximately 1 hour, and approximately 3.5 hours with renal failure.13 Thus, argatroban may be more appropriate for patients in this instance with renal insufficiency or renal failure.

A dosing regimen is essential during procedures where timing of the anticoagulation effect is critical and does not allow for gradual titration adjustments used during longer-term therapy. Smedira et al utilized an intravenous bolus dose of 0.75 mg/kg followed by a continuous infusion at 1.75 mg/kg/hr to maintain an ACT greater than 300 seconds for the duration of off-pump coronary artery bypass.2 Our slight modification of the bolus dose and maintenance infusion to 0.5 mg/kg and 1.0 mg/kg/hr, respectively, resulted in a prompt level of anticoagulation with doubling of the baseline ACT within a few minutes, allowing safe cross clamping for the duration of the procedure, consistent with the peak effect of bivalirudin at approximately 5 minutes after bolus.13

The infusion was reduced after 93 minutes with cross clamp removal and reperfusion, and within 15–30 minutes after discontinuation, it was noted that the coagulation parameters were recovering with no significant suture line bleeding or bleeding through the Dacron patch. This is consistent with bivalirudin’s short elimination half-life of 25 minutes.13 Maintenance of anticoagulation via a continuous infusion in the post-operative period was necessary for several reasons, including the suspected HIT, atrial fibrillation in the setting of a peripheral embolic event, and the recently placed mitral valve. Parameters remained stable as followed by the readily available laboratory parameter aPTT, requiring minimal adjustments in dosing. Overlap of bivalirudin during initiation of warfarin therapy allowed safe transition to oral anticoagulation prior to discharge.

Though not currently approved by the Food and Drug Administration for this use, the American Heart Association/American College of Cardiology guidelines indicate that bivalirudin is useful and effective for patients with HIT who are undergoing percutaneous coronary intervention.15 The use of bivalirudin during peripheral vascular catheter-based interventions has also been successful, though at a higher dosage level than we deemed necessary for open surgery in our case.3 Our experience suggests that bivalirudin can be a safe and effective alternative for use both during open peripheral vascular procedures in a patient with suspected or proven HIT, as well as satisfactory anticoagulation during transition to oral anticoagulation during the postoperative period. To our knowledge, this modified dosing schedule has not been previously described for open peripheral vascular surgery, and in our opinion it can be implemented successfully, especially if monitored with standard, widely available laboratory testing. We would recommend achieving an ACT during operation to twice baseline via bolus then maintaining a continuous infusion until approximately 10 minutes before completion of the arterial closure and restoration of flow. If continued anticoagulation is necessary in the postoperative period, maintenance of the PTT at twice baseline, monitored every 6–12 hours, should be safe and sufficient.

We hope to bring bivalirudin with its rapid onset and shorter half life than lepirudin to the attention of others who may consider it for similar clinical situations. Awareness of the pharmacology and adverse effects will minimize complications, and monitoring with standard laboratory testing provides satisfactory guidelines for use. Further study and experience to assess safety and efficacy in this challenging group of patients is warranted.

Introduction
Advantages of various direct thrombin inhibitors, a modified dosing schedule for bivalrudin, and experience with monitoring parameters are described. These advantages may form the basis for consideration when alternative anticoagulation to heparin is desired during peripheral vascular procedures.

Case ReportAn 82-year-old, 65 kg, white male underwent evaluation for progressive fatigue and shortness of breath. He had undergone a Hancock porcine mitral valve replacement in conjunction with a one-vessel coronary artery bypass 12 years previously. He also had a history of chronic atrial fibrillation, requiring warfarin therapy. After evaluation confirmed significant mitral regurgitation, he was admitted for heparinization and cessation of warfarin therapy prior to “re-do” valve replacement. His preoperative platelet count was 162K/cu mm. He underwent an uncomplicated procedure using a #27 Carpentier-Edwards mitral valve with a concomitant carotid endarterectomy and Dacron patch angioplasty for asymptomatic critical left internal carotid stenosis. Aspirin was begun soon postoperatively. His immediate postoperative platelet count was 80K/cu mm and continued to remain low through the second postoperative day (POD) at 64K/cu mm. Subcutaneous heparin was restarted at 5000 units every eight hours in the evening of POD 2. The platelet count remained low at 68 K/cu mm on POD 3, but his platelet factor 4 (PF4) assay was negative. Coumadin was begun on POD 5, the heparin was discontinued, and a repeat PF4 assay was again negative. By POD 6, the platelet count had increased to 148K/cu mm, and his prothrombin time was 15.5 sec (nl 12.6–15.2); international normalized ratio (INR) was 1.19.

On the seventh POD with an INR of 1.21, he developed sudden onset of the left foot, numbness and calf pain during physical therapy. Initial evaluation suggested a viable functioning limb with no change in pulse status and an audible Doppler signal. However, by the following morning (on POD 8), symptoms had not only progressed but, only a femoral pulse was palpable in the symptomatic limb, which remained cold but appeared viable. Femoral and pedal pulses were palpable in the asymptomatic limb. There was no evidence of aortic or peripheral aneurysms, and the ankle brachial index was reduced to 0.71, but no toe pressure was discernable on the symptomatic extremity.

Though an echocardiogram showed the mitral valve to be well seated without thrombus, a thromboembolic event was suspected, and he was taken directly to the operating room for exploration and angiography without reversal of anticoagulation. Despite previous negative PF4 assays and no serologic evidence of heparin-induced thrombocytopenia (HIT), previous diminished platelet counts and the sudden onset of acute leg ischemia heightened clinical concern about the possibility of serologically negative HIT, as well as concern about using heparin during any attempt at lower extremity revascularization.

Because of these concerns, bivalirudin was used for intraoperative anticoagulation. Evaluation of the patients’ underlying renal function was calculated using the Cockcroft-Gault equation (serum creatinine: 1.1 mg/dl), and was estimated to be approximately 48 ml/min at the time of operation. Since experience using bivalirudin for anticoagulation in patients undergoing off-pump coronary artery bypass operations, percutaneous coronary, and peripheral interventions has been described,1–3 we chose to use a modified version of these dosing strategies to target a lower level of anticoagulation for this open surgical procedure. A bolus dose of bivalirudin 0.5 mg /kg was given intravenously over 10–20 seconds, followed by a continuous infusion of 1.0 mg/kg/hr to achieve and maintain an activated clotting time (ACT), approximately twice baseline (range: 225–250 seconds). Activated clotting times were measured intraoperatively at baseline, 5 minutes after the loading dose given, and then approximately every 15 minutes throughout the procedure. Activated partial thromboplastin time, PT, INR and platelet count were also monitored periodically during the procedure (Table 1). Documentation of an ACT in the predetermined range was confirmed prior to the placement of arterial clamps and the interruption of flow at the femoral level.

The common femoral pulse was excellent, but significant plaque at the common femoral bifurcation necessitated a longitudinal arteriotomy over the bifurcation onto the superficial femoral artery, and an intraoperative arteriogram was performed. Though moderate diffuse atherosclerosis was present in the superficial femoral artery, no flow-limiting plaque was noted at either the arteriotomy or to the level of the popliteal. Filling defects consistent with discontinuous thrombo-emboli were present in the proximal popliteal and posterior tibial vessels. Of note, immediately after the arteriotomy, an alert team member recognized that the standard heparinized saline-irrigating solution already prepared on the field would not be prudent in this setting of possible HIT, and despite the patient’s negative antibody screen, the solution was discarded.
Successful thromboembolectomy was accomplished with retrieval of organized thrombus from both the popliteal and tibial levels, but no “white clot” suggestive of platelet aggregate, suggesting an embolic — rather than thrombotic — event. Repeat angiography revealed moderately diseased, irregular but patent, superficial femoral, popliteal, and peroneal, and posterior tibial vessels without significant distal stenosis or residual thrombus, though the anterior tibial appeared occluded. Thus, the need for direct popliteal exploration or bypass was avoided. The bivalirudin infusion was reduced to 0.1 mg/kg/hr after Dacron patch closure of the arteriotomy was completed with a running suture. Following removal of the arterial clamp and restoration of flow, hemostasis was clinically satisfactory within 30 minutes of reducing the bivalirudin infusion and completion of the arterial closure, with continued correction in coagulation parameters.

Postoperatively the patient had full return of palpable pedal pulses. He was maintained on a continuous bivalirudin infusion at 0.1 mg/kg/hr with titration to maintain a PTT of approximately 2–2.5 times his baseline value (goal: 60–80 seconds) to allow for transition to warfarin for long-term anticoagulation (Table 2). Warfarin was re-initiated the night of surgery without a loading dose, and a daily dose of 5 mg was given until the INR was greater than 2.0. No wound hematoma was evident and perfusion was maintained. His level of anticoagulation on bivalirudin was remarkably stable, requiring only one dosage adjustment to 0.12 mg/kg/hr over the course of therapy. Cessation of the bivalirudin on POD 3 following leg revascularization transiently decreased the INR to 1.63, requiring brief re-initiation of bivalirudin for several hours. A repeat INR on POD 4 following leg revascularization was 2.09. Bivalirudin was discontinued at this time, and the patient was discharged on warfarin 5 mg, alternating with 7.5 mg daily. The final pathology report was consistent with only organized thrombus. He remained asymptomatic with palpable pedal pulses three months post discharge.

Discussion
Direct thrombin inhibitors are assuming an increasing role in the management of suspected HIT to reduce thrombo-embolic complications.4,5 Although anticoagulation with heparin is the generally accepted method of preventing thrombus formation during the performance of cardiac and peripheral vascular procedures, in the setting of suspected HIT — with or without heparin-PF4 antibodies — standard heparinization is not a safe option. Alternatives are limited, and in such settings, the use of the recombinant direct thrombin inhibitors, lepirudin, bivalirudin and argatroban during cardiopulmonary bypass has been described.6–9 However, these intense dosages needed for cardiopulmonary bypass do not translate directly to a relatively lower intensity of anticoagulation required for peripheral vascular surgery. To date, the experience with direct thrombin inhibition for anticoagulation among patients requiring vascular procedures has been even more recent and limited.10,11 While a more aggressive anticoagulation regimen with either re-initiation of heparin or direct thrombin inhibitors following mitral valve replacement in the setting of atrial fibrillation may have obviated this post-operative thromboembolic event, this controversy remains beyond the impetus of this discussion. Rather, our case focuses on delineating not only a safe and effective method of anticoagulation using bivalirudin in a patient with possible HIT requiring lower extremity revascularization, but also maintenance of postoperative anticoagulation for several days, with successful transition to anticoagulation with warfarin.

Although there was no serologic evidence of heparin-induced thrombocytopenia in this case, we were faced with the knowledge that PF4 may not be positive in all cases of HIT. There was a compelling need for systemic anticoagulation in a setting where diminished platelet counts were encountered following and during heparin therapy and a clinical suspicion for HIT remained. We felt that the administration of bivalirudin was a more appropriate choice for use in peripheral vascular procedures in this setting. It is a direct thrombin inhibitor and does not appear to precipitate HIT by cross-reacting with associated heparin-PF4 antibodies. In addition, its pharmacokinetic profile, quick onset, and short half-life make it ideal for use in peripheral vascular procedures as an alternative to heparin or the other thrombin inhibitors.

Unlike heparin, bivalirudin is a direct thrombin inhibitor which reversibly binds to the thrombin active site, bypassing interaction with antithrombin III.12 There are two other direct thrombin inhibitors currently available in the United States, lepirudin and argatroban. All are administered intravenously, and none of the three cross react with the heparin-induced antibody.5 Lepirudin is primarily eliminated by renal excretion with a terminal half life of approximately 1.3 hours.5,12 Argatroban is hepatically cleared with a terminal half life of approximately 39–51 minutes.5 Bivalirudin is cleared both by intravascular proteolysis and renal mechanisms and possesses the shortest elimination half life of approximately 25 minutes.13 There is no reversal for this group of drugs, and their use must be judicious to prevent coagulopathy and bleeding, especially during cardiac and peripheral vascular procedures.5 Thus, bivalirudin appears to offer advantages over lepirudin and argatroban during surgery in patients with adequate renal function. In patients with renal insufficiency, the elimination half life of lepirudin is prolonged (up to 50 hours in renal failure).14 The elimination half life for bivalirudin in patients with moderate renal impairment (creatinine clearance: 10–29 ml/minute) is approximately 1 hour, and approximately 3.5 hours with renal failure.13 Thus, argatroban may be more appropriate for patients in this instance with renal insufficiency or renal failure.

A dosing regimen is essential during procedures where timing of the anticoagulation effect is critical and does not allow for gradual titration adjustments used during longer-term therapy. Smedira et al utilized an intravenous bolus dose of 0.75 mg/kg followed by a continuous infusion at 1.75 mg/kg/hr to maintain an ACT greater than 300 seconds for the duration of off-pump coronary artery bypass.2 Our slight modification of the bolus dose and maintenance infusion to 0.5 mg/kg and 1.0 mg/kg/hr, respectively, resulted in a prompt level of anticoagulation with doubling of the baseline ACT within a few minutes, allowing safe cross clamping for the duration of the procedure, consistent with the peak effect of bivalirudin at approximately 5 minutes after bolus.13

The infusion was reduced after 93 minutes with cross clamp removal and reperfusion, and within 15–30 minutes after discontinuation, it was noted that the coagulation parameters were recovering with no significant suture line bleeding or bleeding through the Dacron patch. This is consistent with bivalirudin’s short elimination half-life of 25 minutes.13 Maintenance of anticoagulation via a continuous infusion in the post-operative period was necessary for several reasons, including the suspected HIT, atrial fibrillation in the setting of a peripheral embolic event, and the recently placed mitral valve. Parameters remained stable as followed by the readily available laboratory parameter aPTT, requiring minimal adjustments in dosing. Overlap of bivalirudin during initiation of warfarin therapy allowed safe transition to oral anticoagulation prior to discharge.

Though not currently approved by the Food and Drug Administration for this use, the American Heart Association/American College of Cardiology guidelines indicate that bivalirudin is useful and effective for patients with HIT who are undergoing percutaneous coronary intervention.15 The use of bivalirudin during peripheral vascular catheter-based interventions has also been successful, though at a higher dosage level than we deemed necessary for open surgery in our case.3 Our experience suggests that bivalirudin can be a safe and effective alternative for use both during open peripheral vascular procedures in a patient with suspected or proven HIT, as well as satisfactory anticoagulation during transition to oral anticoagulation during the postoperative period. To our knowledge, this modified dosing schedule has not been previously described for open peripheral vascular surgery, and in our opinion it can be implemented successfully, especially if monitored with standard, widely available laboratory testing. We would recommend achieving an ACT during operation to twice baseline via bolus then maintaining a continuous infusion until approximately 10 minutes before completion of the arterial closure and restoration of flow. If continued anticoagulation is necessary in the postoperative period, maintenance of the PTT at twice baseline, monitored every 6–12 hours, should be safe and sufficient.

We hope to bring bivalirudin with its rapid onset and shorter half life than lepirudin to the attention of others who may consider it for similar clinical situations. Awareness of the pharmacology and adverse effects will minimize complications, and monitoring with standard laboratory testing provides satisfactory guidelines for use. Further study and experience to assess safety and efficacy in this challenging group of patients is warranted.